Electrically excitable cells are the building blocks of the nervous system and the cardiovascular system. Electrical excitability is the basis for the generation of rapid signalling between cells and the signal processing properties of the cells of the nervous system. It is also the basis for initiating the contraction of the muscle of the heart and the vascular smooth muscle that controls blood pressure. Electrical excitability arises from the ability of ions (i.e., sodium, potassium, and calcium) to rapidly move across channels bridging the inside and the outside of the cell. Because ions are electrically charged, the rapid movements of ions generate electric currents. The regulation of the conductances of these channels determines the electrical excitability of the cell. There are a number of different ionic channels in each cell. Each channel has its own distinct characteristics and plays distinct roles. Together they operate as an ensemble that serves to control the electrical behavior of the cell.
In living cells, an electrical potential exists between the inside and outside of the cell This potential difference is called the membrane potential. At-rest electric potential on the inside of a typical cell is 60 to 80 millivolts more negative than the outside. Living cells also maintain the ionic composition of the cytoplasm to be different from that of the extracellular fluid. The concentration gradients for the ions between the inside and outside of the cell create the driving forces for the flow of ions through ionic channels. Calcium and sodium ions are maintained at very low concentration inside the cell compared to the outside. The reverse is true for potassium ions. If the calcium conducting channels (calcium channels) bridging the inside and outside of the cell are to open, there will be a rapid influx of calcium ion into the cell. The same is true for sodium and the sodium channel.
On the other hand, if the potassium channel is to open, potassium ions will rapidly flow out of the cell. Because these cations carry electric charges, the flux of ions generate an electric current. This current, in turn, controls the electrical potential difference between the inside and the outside of the cell (the membrane potential). When either the sodium or the calcium channel opens, cations enter the cell. This influx of positive charges causes the membrane potential to become more positive relative to its normal, resting membrane potential and the cell "depolarizes" or approaches the point at which it has no electrical charge. On the other hand, opening of the potassium channel leads to cations leaving the cell and a more negative membrane potential.
In order for neurons to generate an action potential and avoid the ionic gradient from rapidly running down, the ionic channel conductances are carefully controlled. The conductances of these channels are in turn tightly controlled by the membrane potential. At the resting membrane potential, most ion channels are closed. But if the membrane potential is depolarized to a certain point, the channel will open. The sodium channel, for example, will open when the membrane potential is depolarized to its threshold potential of -40 millivolts. The resulting influx of positively charged sodium ions leads to further membrane depolarization and further sodium channels openings. This regenerative depolarization results in the "action potential." The action potential is the basic signal within the nervous system. After opening, the sodium channels close rapidly. In the meantime, the slower responding potassium channels open in response to the membrane depolarization and bring the cell back to its resting membrane potential. The calcium channel is similar to the sodium channel in its ability to contribute to membrane depolarization, since opening of the calcium channels will result in a net influx of positively charged calcium ions.
Different types of channels have different biophysical properties. This heterogeneity of channel behavior permits differing physiologic roles for these channels. There are at least two types of voltage dependent calcium channels, the T and the L channel. They can be distinguished based on their voltage range of activation and their inactivation kinetic characteristics. The L type channel requires full membrane depolarization before activation, whereas the T type channels require only weak depolarization for activation. The T channel is activated at membrane potentials which are close to the resting membrane potential and near the membrane potentials for sodium channel activation. Besides contributing to neuronal excitability, calcium influx into neurons via ion channels is central to man aspects of neuronal function and dysfunction. These roles include control of neurotransmitter release, and regulation of calcium dependent intracellular enzymatic processes and second messenger roles. Excess calcium influx has also been shown to lead to neuronal death.
Pharmacologic agents that preferentially inhibit movement of calcium ions through voltage activated calcium channels are called calcium channel blockers. Three calcium channel blockers are presently approved for clinical use in the United States, nifidepine, verapamil, and diltiazem. These calcium channel blockers are highly potent in blocking the calcium channels in vascular smooth muscle and cardiac muscle. They are approved for use in treating angina, hypertension, and cardiac arrhythmia. They have also been effective in preventing coronary and cerebral vasospasm, and for use in treating migraine headaches. These calcium channel blockers, however, are much less effective on the calcium channels of neurons and also cause unacceptable side effects such as oversedation due to depression of neuronal function. Consequently, calcium channel blockers which are more effective in the nervous system are needed to treat a number of neurologic disorders that have already shown some responsiveness to the presently available calcium channel blockers. Furthermore, available calcium channel blockers lack selectivity for the different types of neuronal calcium channels. Nifidepine blocks only the L type calcium channel which predominates in the heart. Verapamil and diltiazem block both the L and T type calcium channels, but have less potency when studied in neurons. Thus calcium channel blockers which can selectively suppress the T type calcium channel without suppressing the L type channel ar needed to minimize the unwanted side effects that result from suppression of the L type channel when available calcium channel blockers are used to treat neurologic disorders.
Epilepsy is one neurologic disorder which has shown responsiveness to available calcium channel blockers. The clinical usefulness of these compounds, however, has been limited by unacceptable side effects, the most significant of which is oversedation. The exact cellular mechanisms causing epilepsy have not been clearly established, however, it has been shown that calcium channels mediate one of the major intrinsic mechanisms for generating the abnormal hyperexcitable behavior of neurons at the seizure focus. Recently, the prototypic anticonvulsant, diphenylhydantoin, has been shown to possess the property of suppressing the T type calcium channel. This may well be the mechanism for diphenylhydantoin,s well established anticonvulsant properties.
The pharmacologic treatment of painful neuropathies and central pain syndromes has employed many of the same compounds used in treating epilepsy including diphenylhydantoin. Both conditions are manifested by hyperexcitable neuronal behavior. Because of the role of the T type calcium channel in contributing to near threshold membrane excitability, selective suppression of the T channel will decrease neuronal hyperexcitability and raise the threshold for the perception of pain. Thus, there is a long-felt need for calcium channel blocking compositions which are selective for the T type calcium channel.